Nociceptive transient receptor potential ankyrin 1 (TRPA1) in sensory neurons are targets of the antifungal drug econazole
Kaoru Kasuya1, Kenji Takahashi1,2, Miho Hashimoto2 and Toshio Ohta1,2*
Abstract
Background Econazole is a widely used imidazole derivative antifungal for treating skin infections. The molecular
targets for its frequent adverse effects of skin irritation symptoms, such as pruritus, burning sensation, and pain, have
not been clarified. Transient receptor potential (TRP) channels, non-selective cation channels, are mainly expressed in
peripheral sensory neurons and serve as sensors for various irritants.
Methods We investigated the effect of econazole on TRP channel activation by measuring intracellular calcium
concentration ([Ca2+]i) through fluorescent ratio imaging in mouse dorsal root ganglion (DRG) neurons isolated from
wild-type, TRPA1(−/−) and TRPV1(−/−) mice, as well as in heterologously TRP channel-expressed cells. A cheek injection
model was employed to assess econazole-induced itch and pain in vivo.
Results Econazole evoked an increase in [Ca2+]i, which was abolished by the removal of extracellular Ca2+ in mouse
DRG neurons. The [Ca2+]i responses to econazole were suppressed by a TRPA1 blocker but not by a TRPV1 blocker.
Attenuation of the econazole-induced [Ca2+]i responses was observed in the TRPA1(−/−) mouse DRG neurons but was
not significant in the TRPV1(−/−) neurons. Econazole increased the [Ca2+]i in HEK293 cells expressing TRPA1 (TRPA1-
HEK) but not in those expressing TRPV1, although at higher concentrations, it induced Ca2+ mobilization from
intracellular stores in untransfected naïve HEK293 cells. Miconazole, which is a structural analog of econazole, also
increased the [Ca2+]i in mouse DRG neurons and TRPA1-HEK, and its nonspecific action was larger than econazole.
Fluconazole, a triazole drug failed to activate TRPA1 and TRPV1 in mouse DRG neurons and TRPA1-HEK. Econazole
induced itch and pain in wild-type mice, with reduced responses in TRPA1(−/−) mice.
Conclusions These findings suggested that the imidazole derivatives econazole and miconazole may induce skin
irritation by activating nociceptive TRPA1 in the sensory neurons. Suppression of TRPA1 activation may mitigate the
adverse effects of econazole.
Keywords Antifungal, Heterologous expression, Intracellular Ca2+ concentration, Nociceptor, Sensory neuron,
Transient receptor potential channel
